反应详情

温度

100 °C

A 1-L round-bottomed flask was charged with (5-((1R)-1-((2S)-4-(tert-butoxycarbonyl)-2-methyl-1-piperazinyl)ethyl)-2-fluoro-3-pyridinyl)boronic acid (11.90 g, 32.4 mmol), 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 51; 13.72 g, 35.6 mmol), KOAc (10.18 g, 104 mmol), dioxane (180 mL), and water (36.0 mL). Nitrogen gas was bubbled through the mixture for 10 min. Bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (2.295 g, 3.24 mmol) was added and a reflux condensor was attached to the flask. The mixture was heated at 100° C. under nitrogen overnight (17 h). After cooling to ambient temperature, water was added and the mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. The crude material was adsorbed onto silica gel and purified by column chromatography (330 g of silica gel, 5% to 75% EtOAc/hexanes) to give tert-butyl(3S)-4-((1R)-1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate (13.35 g, 19.87 mmol, 61.3% yield) as a light-yellow foam. m/z (ESI, +ve) 672.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.39-8.46 (m, 1H) 8.19-8.24 (m, 1H) 7.19-7.25 (m, 4H) 6.83-6.90 (m, 4H) 4.82 (d, J=11.93 Hz, 4H) 3.97-4.07 (m, 1H) 3.81 (s, 3H) 3.80 (br s, 1H) 3.79 (s, 3H) 3.31-3.44 (m, 2H) 3.08-3.18 (m, 1H) 2.69-2.77 (m, 1H) 2.55 (s, 3H) 2.42-2.48 (m, 2H) 1.39-1.46 (m, 12H) 1.00 (d, J=6.26 Hz, 3H).

1. customNitrogen gas was bubbled through the mixture for 10 min
2. temperatureAfter cooling to ambient temperature
3. extractionthe mixture was extracted with EtOAc (3×200 mL)
4. dry with materialThe combined organic extracts were dried over anhydrous Na2SO4
5. filtrationfiltered
6. concentrationconcentrated
7. custompurified by column chromatography (330 g of silica gel, 5% to 75% EtOAc/hexanes)